CN103622982A - Application of ginsenoside Rg1 in preparation of medicine for preventing antiendotoxin from acting on Toll-like receptor 4 - Google Patents
Application of ginsenoside Rg1 in preparation of medicine for preventing antiendotoxin from acting on Toll-like receptor 4 Download PDFInfo
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Abstract
The invention discloses application of ginsenoside Rg1 in preparation of a medicine for preventing antiendotoxin from acting on a Toll-like receptor 4. The ginsenoside Rg1 can prevent antiendotoxin from combining onto a Toll-like receptor 4 in a mammal, so as to block off a toxic effect of bacterial endotoxin and alleviating an acute inflammation process caused by LPS.
Description
Technical field
The present invention relates to the purposes of ginsenoside Rg1, especially for preparation opposing endotoxin, act on the medicine on Toll sample receptor 4.
Background technology
The cell wall lipopolysaccharide composition lipopolysaccharide(LPS that bacterial endotoxin (endotoxin) discharges while being gram negative bacteria cracking), be the main pathogenic [1] that causes humans and animals sepsis or septic shock.The sick learning of Foreign Epidemic investigated demonstration, and the sepsis patient in the annual whole world surpasses the 1800 Wan Li， U.S. approximately 750,000 examples, and America and Europe dies from this sick number every year over 350,000, is the modal cause of the death in ICU ward [2,3].China still lacks detailed epidemiologic data at present.It is estimated that to have every year 3000000 cases at least, therefore sick and dead number is in more than 1,000,000 [3].Zoogenetic infection gram negative bacteria is also extremely general, is found in the various animals such as pig, cattle, sheep, horse, deer, Moschus moschiferous, Vulpes, camel, mink, giant panda.Although different animals clinical symptoms is not quite similar, can show as the acute inflammatory reaction that endotoxin causes.For example, the super acute mastitis (peracute mastitis) that milch cow escherichia coli cause.Can there is the acute inflammation symptom of the local and whole body of breast in sick cattle, show as breast and nipple part red, swollen, hot, bitterly, can not squeeze milk, whole body fervescence, lethargy, loss of appetite or give up exhausted [4,5].As rescued not in time, can cause that disease cattle is dead, or ill mammary gland tissue is subject to heavy damage, causes blind teat, cause serious economic loss [4].
In recent years to bacterial endotoxin cause inflammation reaction pathomechanism carried out large quantity research.Think that at present it is the main cause [6] that causes endotoxin induction systemic inflammatory response that host produces excessive immunoreation to the cause of disease of intrusion body.Cracking when gram negative bacteria is dead, discharge LPS, the lipopolysaccharide binding protein LBP in blood and LPS combination, pass to LPS the CD14 of Macrophage Surface, forms CD14-LPS[7].Myeloid differential protein-2(MD-2 in macrophage membrane) and Toll sample receptor 4(TLR4) in conjunction with forming MD2-TLR4, there is pattern recognition effect [7,8,9].After TLR4 identification LPS, form TLR4-MD2-LPS complex, the three-dimensional conformation of TLR4 changes, in its born of the same parents, the TIR domain of part is done to transduce with adaptin MyD88 effect enabling signal by homotype mutually, the adaptin TRAM that inclusive NAND MyD88 relies on and TRIF effect activate NF-к B, induction macrophage synthesizes and secretion IL-1, IL-6, the cytokines such as IFN-β and TNF-α, they enter after blood circulation arrives hypothalamus and act on thermotaxic centre, make to move on set point, cause organism fever [10].The inflammatory reactions such as these are discharged into extracellular cytokine and also cause granulocyte, macrophage Chemotaxis, and capillary permeability increases, lymphocytic infiltration.Another consequence that LPS continues to stimulate is Th1 type cytokines (TNF-α, IFN-γ) secretion reduces, and Th2 type cytokines (IL-4, IL-10) increases, the stimulation nonreply of T cell to specific antigen, cause immunological paralysis, immune system is removed the defunctionalization [11] of cause of disease.
The treatment of the inflammatory reaction at present bacterial endotoxin being caused mainly adopts the generation [12] of antibiotic infection control source and the glucocorticoid inflammation-inhibiting factor.But research discovery antibiotic therapy can be induced the generation of endotoxemia, its reason is after antibiotic therapy, to cause that a large amount of antibacterials is dead, discharges LPS, and the LPS in circulation is increased, and increases the weight of systemic inflammatory reaction [13]; Glucocorticoid can suppress the immune system of body, is unfavorable for that antibacterial infects clear.Because bacterial endotoxin is pathogenic extremely general, world Ge great drugmaker competitively researches and develops antiendotoxin medicine.One of them thinking is to adopt TLR4 antagonist to suppress by blocking-up TLR4 signal path the inflammatory reaction that LPS causes.Eritoran(E5564) and TAK-242 be exactly the representative of this class medicine.E5564 is the compound of Eisai drugmaker exploitation, is similar to the lipoid A in endotoxin in structure.E5564 in vitro with the hydrophobic region combination of MD-2 molecule, competitively stop lipoid A in endotoxin to be attached to this position, and then the proinflammatory effect [14,7] of blocking-up LPS; TAK-242 is the cyclohexene derivative of Takeda drugmaker exploitation, and it can optionally be combined in the intracellular region TIR domain of TLR4, by suppressing the phosphorylation blocking-up TLR4 signal transduction [7] of TRAM.Animal experiment shows, E5564 and TAK-242 can significantly suppress the generation of the endotoxemia of LPS induction, and by I phase and II clinical trial phase [7], but because they do not have remarkable therapeutic effect to serious toxemia patient, not by III clinical trial phase [7].Therefore, there is no clinically at present the endotoxic specific treatment medicine of directed toward bacteria.
Ginsenoside Rg1, English name Ginsenoside Rg1, it has the Hippocampus of promotion nerve the effects such as neural plasticity, enhancing study, memory, defying age, resisting fatigue, raising immunity, auxiliary antitumor, reparation sexual function occurs, improves, and aspect the neurodegenerative diseases such as high-end health care, auxiliary antitumor, control senile dementia, is having broad application prospects.
The affecting of the < < ginsenoside Rg 1 on pulmonary vascular permeability in acute lung injury induced by lipopolysaccharide that the authors such as Xiong Jun delivered in 2006 infers in > > mono-literary composition that to reduce induced lung edema that experimental LPS causes be by antioxidation to Rg1 and maintain the stability of cell membrane; In medication, for taking to inject Rg1 in injection LPS.
The list of references above relating to is specific as follows:
[1] Tian Jinfei, Tang Yan, Shiyan. pyemia progress. the anxious critical illness magazine of internal medicine, 2012,18 (1): 14-16;
[2] T Lagu, MB Rothberg, MS Shieh, PS Pekow, JS Steingrub, PK Lindenauer.What is the best method for estimating the burden of severe sepsis in the United States Journal of Critical Care2012,27:414.e1 – 414.e9(T Lagu, MB Rothberg, MS Shieh, PS Pekow, JS Steingrub, what the best method that PK Lindenauer. evaluates Severe sepsis final result in the U.S. is. Intensive Care Therapy magazine 2012,27:414.e1 – 414.e9);
[3] Yao Yongming, Sheng Zhiyong. sepsis is anti-makes a study of subjects. scientific and technical literature publishing house, Beijing,, the 1st edition in 2008;
[4] Ding Bailiang, Feng Jianzhong, Zhang Guowei. mammitis of cow, Chinese agriculture publishing house, Beijing,, the 1st edition in 2011;
[5] O Wellnitz, RM Bruckmaier.The innate immune response of the bovine mammary gland to bacterial infection.The Veterinary Journal2012,192:148 – 152(O Wellnitz, the immunoreation that RM Bruckmaier. bovine mammary gland infects antibacterial. veterinary's magazine 2012,192:148 – 152);
[6] A Kotsaki, EJ Giamarellos-Bourboulis.Emerging drugs for the treatment of sepsis.Expert Opin.Emerging Drugs, 2012,17 (3): 379-391(A Kotsaki, the new drug of EJ Giamarellos-Bourboulis. treatment pyemia. the expert opinion 2012,17 (3) of new drug: 379-391);
[7] I Brodsky, R Medzhitov.Therapeutic targeting of innate immunity with Toll-like receptor4 (TLR4) antagonists.Biotechnology Advances2012,30:251 – 260(I Brodsky, R Medzhitov. is for the medicine of natural immunity receptor TLR4. biotechnology progress 2012,30:251 – 260);
[8] I Brodsky, R Medzhitov.Two Modes of Ligand Recognition by TLRs.Cell2007,130:979-981(I Brodsky, two kinds of patterns of R Medzhitov. part identification TLRs. cell 2007,130:979-981);
[9] HM Kim, BS Park, JI Kim, SE Kim, JD Lee, SC Oh, P Enkhbayar, N Matsushima, HY Lee, OJ Yoo, JO Lee.Crystal Structure of the TLR4-MD-2Complex with Bound Endotoxin Antagonist Eritoran.Cell2007, 130:906 – 917(HM Kim, BS Park, JI Kim, SE Kim, JD Lee, SC Oh, P Enkhbayar, N Matsushima, HY Lee, OJ Yoo, JO Lee.TLR4-MD-2 and Endotfoxin antagonist Yi Lituolun are in conjunction with the crystal structure of complex. cell 2007, 130:906 – 917),
[10] R Song, J Kim, D Yu, C Park, J Park.Kinetics of IL-6and TNF-α changes in a canine model of sepsis induced by endotoxin.Veterinary Immunology and Immunopathology2012,146:143 – 149(R Song, J Kim, D Yu, C Park, J Park.IL-6 and the TNF-α variation in endotaxin induction toxemia dog body. veterinary immunology and immunopathology 2012,146:143 – 149);
[11] EJ Giamarellos-Bourboulis, M Raftogiannis.The immune response to severe bacterial infections:consequences for therapy.Expert Rev.Anti Infect.Ther.2012,10 (3): 369-380(EJ Giamarellos-Bourboulis, the immunoreation that M Raftogiannis. severe bacterial infections causes: therapeutic outcome. anti-infective therapy's comment 2012,10 (3): 369-380);
[12] He LingYun， Tang is along red. the treatment new development of pyemia. and Jilin medical science, 2012,33(11): 2338-2339;
[13] Zhang Yongyi, Guo Changxing. antibiotic inducing endotoxin mass formed by blood stasis progress. Chinese general family medicine, 2008,6(12): 1297-1298;
[14] SH Park, ND Kim, JK Jung, CK Lee, SB Han, YS Kim.Myeloid differentiation2as a therapeutic target of inflammatory disorders.Pharmacology & Therapeutics2012,133:291 – 298(SH Park, ND Kim, JK Jung, CK Lee, SB Han, YS Kim.MD2 is as the treatment target spot of inflammation disease. pharmacology and therapeutics 2012,133:291 – 298).
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of new purposes of ginsenoside Rg1---ginsenoside Rg1 for the preparation of anti-endotoxin effect in the medicine of Toll sample receptor 4.
In order to solve the problems of the technologies described above, to the invention provides ginsenoside Rg1 and preparing the application of anti-endotoxin effect on Toll sample receptor 4 medicines.
As ginsenoside Rg1 of the present invention in the improvement of preparing the application of anti-endotoxin effect on Toll sample receptor 4 medicines: ginsenoside Rg1 can stop endotoxin to be attached to the Toll sample receptor 4 in mammalian body, thus the toxic action of blocking-up bacterial endotoxin.
The present invention has adopted ginsenoside Rg1 has been dissolved in to water, makes aqueous solution; And experimental verification with this solution, to resisting endotoxin after animal injection, act on Toll sample receptor 4.
Inventor learns in invention process: ginsenoside Rg1 can stop endotoxin to be attached to the Toll sample receptor 4 in mammalian body, thereby the toxic action of blocking-up bacterial endotoxin is brought into play the effect of anti-LPS; That is, thus for realizing Nnti-Bacterial endotoxin; In the heating that realization alleviation bacterial endotoxin causes, blood, inflammatory factor raises and death.
In order to prove above-mentioned effect of the present invention, experiment of the present invention all before injection LPS or inject afterwards Rg1, therefore approaches truth more, fully proves that Rg1 can prevent or treat the damage that LPS causes.
Actual usage and the consumption of ginsenoside Rg1 are: ginsenoside Rg1 is made to injection, and for intravenous injection, intramuscular injection, subcutaneous injection or lumbar injection, per injection dosage is 0.5～5mg/Kg body weight, injects every day 2～3 times.
Advantage of the present invention
In the present invention, adopt ginsenoside Rg1 to be attached on the interior TLR-4 receptor of mammalian body, the effect of blocking-up LPS, alleviates the acute inflammation process that LPS causes.
Accompanying drawing explanation
Below in conjunction with accompanying drawing, the specific embodiment of the present invention is described in further detail.
Fig. 1 is the lethal effect figure of ginsenoside Rg1 prevention LPS to mice;
Fig. 2 is the therapeutical effect figure of ginsenoside Rg1 to LPS poisoning mice;
Fig. 3 is the pyrogenic action figure of ginsenoside Rg1 prevention LPS to rat;
Fig. 4 is that ginsenoside Rg1 prevention LPS causes the action diagram that blood leucocyte sum raises;
Fig. 5 is that ginsenoside Rg1 prevention LPS causes the action diagram that blood neutrophil raises;
Fig. 6 is that ginsenoside Rg1 prevention LPS causes the action diagram that serum NO level raises;
Fig. 7 is that ginsenoside Rg1 prevention LPS causes the action diagram that serum PG E2 raises;
Fig. 8 is the affect figure of ginsenoside Rg1 on ehec infection rabbit body temperature;
Fig. 9 is the affect figure of ginsenoside Rg1 on ehec infection rabbit blood total white blood cells;
Figure 10 is the affect figure of ginsenoside Rg1 on ehec infection rabbit blood neutrophil number;
Figure 11 is the affect figure of ginsenoside Rg1 on ehec infection rabbit blood TNF-α;
Figure 12 is the affect figure of ginsenoside Rg1 on ehec infection rabbit blood IL-1 β;
Figure 13 is the affect figure of ginsenoside Rg1 on ehec infection rabbit blood IL-6;
Figure 14 is that ginsenoside Rg1 produces the inhibitory action figure of pro-inflammatory cytokine and inflammatory mediator mrna expression to LPS induction RAW264.7 cell;
Figure 15 is Rg1 blocking-up LPS and RAW264.7 Cell binding figure.
The specific embodiment
The dead mouse effect that causes of embodiment 1, ginsenoside Rg1 prevention LPS
60 BALB/c mouse (purchased from Shanghai country rodent kind subcenter) are divided into 6 groups at random, and 10 every group, grouping and processing are in Table 1.Group 1～4 mouse subcutaneous injection Rg1(is purchased from Hong Jiu biotech inc, Jilin) normal saline solution, dosage is respectively 7.5,15,30,60mg Rg1/kg body weight, organizes 5～6 injected in mice normal saline, liquid medicine injection volume is 100 μ l.Drug injection finishes latter 15 minutes, organizes 1～5 once abdominal cavity injection LPS(purchased from Sigma company), dosage is 20mg/kg body weight (being mixed with in advance every milliliter containing the normal saline solution of 50mg LPS), organizes the normal saline of 6 lumbar injection same volume accumulated amounts.Activity and the death condition of observing mice in 60 hours, the results are shown in Figure 1.As shown in Figure 1, organize 6 mices 100% survivals, and the survival rate of organizing 5 mices only has 30%, illustrates that LPS has lethal effect to mice; The mice (organizing 3,4) of injecting in advance 30mg/kg and 60mg/kg Rg1 does not have death, obtains 100% protection; The survival rate of injecting in advance the mice (organizing 1,2) of 7.5mg/kg and 15mg/kg Rg1 is respectively 60% and 90%, obtains part protection.
Table 1, grouping and processing
30 BALB/c mouse (purchased from Shanghai country rodent kind subcenter) are divided into 3 groups at random, and 10 every group, grouping and disposition are in Table 2.Group 1-2 mouse peritoneal injection LPS(is purchased from Sigma company), dosage is that 20mg/kg(is mixed with every milliliter in advance containing the normal saline solution of 50mg LPS), organize the normal saline of 3 injected in mice same volume accumulated amounts.After 15min, organize 1 mouse subcutaneous injection Rg1(purchased from Hong Jiu biotech inc, Jilin) 30mg/kg, organize 2 and group 3 mouse subcutaneous injection normal saline, volume injected is 100 μ l.Activity and the death condition of observing mice in 60 hours, the results are shown in Figure 2.As shown in Figure 2, the survival rate of organizing 3 mices is 100%, and the survival rate of organizing 2 mices is 30%, illustrates that LPS lumbar injection has lethal effect to mice; Organize after 1 injected in mice Rg1, survival rate is increased to 90%, and illustrating that mice that Rg1 causes LPS is poisoning has a therapeutical effect.
Table 2, grouping and processing
The rat body inflammatory reaction that embodiment 3, ginsenoside Rg1 prevention LPS cause
18 male SD rats are divided into 3 groups at random, 6 every group.Organize 1 rat tail vein injection ginsenoside Rg1 (purchased from Hong Jiu biotech inc, Jilin), dosage is 1mg/kg; Group 2 and group 3 rat intravenous injection normal saline, volume injected is 100 μ l.After 15 minutes, organize 1 and group 2 tail vein injection LPS(purchased from Sigma company), dosage is 2.5mg/kg; Organize 3 injecting normal salines, volume injected is 100 μ l.
Administration first 2 hours and 1 hour, measures rectal temperature, averages as the basal body temperature before administration.After administration in 4 hours every 15 minutes, 4 hours to 8 hours every 1 hour, detects rectal temperature; Before administration with after administration, within 2,4,6 and 8 hours, gather anticoagulant blood examination hemocyte (IDEXX Automatic Blood Cell Analyzer, U.S. Ai Deshi biotechnology company); Blood sample collection, prepare serum, detect cytokine (TNF-α, IL-1 β and IL-6) (detectable is purchased from Santa Cruz company), inflammation regulatory factor (COX-2, iNOS) (detectable is purchased from Santa Cruz company), nitric oxide NO(test kit is purchased from the green skies, Jiangsu biotechnology research institute) and PGE2(test kit purchased from R & D company).
The pyrogenicity effect of ginsenoside Rg1 prevention LPS is shown in Fig. 3.As seen from Figure 3, to rat injection LPS, can cause fervescence.But before injection LPS, inject Rg1, the fervescence effect that LPS causes reduces greatly, and the pyrogenic action that ginsenoside Rg1 can prevent LPS to cause is described.
Fig. 4 is shown in the effect that ginsenoside Rg1 prevents LPS to cause that blood leucocyte sum raises, and Fig. 5 is shown in the effect that ginsenoside Rg1 prevents LPS to cause that blood neutrophil raises.From Fig. 4 and Fig. 5, injection LPS can cause that animal blood total white blood cells and neutrophil quantity raise, and injected Rg1 before injection LPS, the total white blood cells that LPS causes and neutrophilia bag cell quantity rising meeting reduce greatly, illustrate that ginsenoside Rg1 can prevent the blood leucocyte sum that LPS causes to raise and the rising of neutrophil quantity.
Fig. 6 is shown in the effect that ginsenoside Rg1 prevents LPS to cause that serum inflammatory cytokine NO raises, and Fig. 7 is shown in the effect that ginsenoside Rg1 prevents LPS to cause that serum inflammatory cytokine PGE2 raises.From Fig. 6 and Fig. 7, injection LPS can cause that animal serum NO raises and PGE2 raises, and injected Rg1 before injection LPS, the serum NO level that LPS causes raises and PGE2 rising effect meeting reduces greatly, and serum inflammatory cytokine NO and PGE2 rising effect that ginsenoside Rg1 can prevent LPS to cause are described.
Embodiment 4: the therapeutical effect of ginsenoside Rg1 to rabbit coli-infection
Remarks explanation: LPS is the main component of Bacillus coli cells wall, coliform infects after human body or animal, cracking when antibacterial is dead, discharges LPS, enters blood, causes the inflammatory reaction of body.The object that the present embodiment is set is also effective to treatment coli-infection in order to prove Rg1.
10 new zealand white rabbits are divided into 2 groups at random, 5 every group.Every rabbit is in 2 milliliters of escherichia coli suspensions (10 of cervical region subcutaneous injection
9cFU/ml), one group of rabbit intravenous injection Rg1 then, dosage is 12mg/kg; Another group is matched group, injecting normal saline, and volume injected is 0.2ml.At 3 rectal temperatures of test before measurement, average as basal body temperature, infect in latter 48 hours every a body temperature of survey in 1 hour.Within after infecting 2,4,6 and 8 hours, gather anticoagulant blood examination hemocyte (IDEXX Automatic Blood Cell Analyzer, U.S. Ai Deshi biotechnology company); Blood sample collection, prepares serum, detects cytokine (TNF-α, IL-1 β and IL-6) (detectable is purchased from Santa Cruz company) and LPS concentration.
Ginsenoside Rg1 is shown in Fig. 8 to the impact of ehec infection rabbit body temperature.As seen from Figure 8, rabbit ehec infection can cause fervescence.But after having injected Rg1, fervescence effect reduces, and illustrates that ginsenoside Rg1 has reducing effect to the rising body temperature of ehec infection rabbit.
Ginsenoside Rg1 is shown in Fig. 9 to the effect of ehec infection rabbit blood total white blood cells, and ginsenoside Rg1 is shown in Figure 10 to the effect of ehec infection rabbit blood neutrophil.From Fig. 9 and Figure 10, rabbit has infected blood leucocyte sum and the rising of neutrophil quantity after escherichia coli, and total white blood cells and neutrophilia bag cell quantity rising meeting reduce greatly after having injected Rg1, illustrate that ginsenoside Rg1 causes that to coli-infection blood leucocyte sum and the neutrophil quantity of rising have reducing effect.
Ginsenoside Rg1 is shown in respectively Figure 11, Figure 12 and Figure 13 to the effect of ehec infection rabbit anteserum cytokine TNF-α, IL-1 β and IL-6.From Figure 11-13, rabbit can cause that serum cytokines TNF-α, IL-1 β and IL-6 raise after having infected escherichia coli, and greatly reduce having injected serum cytokines TNF-α, IL-1 β and IL-6 rising effect meeting after Rg1, illustrate that the serum cytokines rising that ginsenoside Rg1 causes coli-infection has reducing effect.
Embodiment 5: the inhibitory action of ginsenoside Rg1 to LPS induction Expression of Macrophages pro-inflammatory cytokine and inflammatory mediator
It is 1 * 10 that mouse macrophage RAW264.7 is adjusted to cell concentration with fresh serum-free medium
7individual cell/ml.Then in 6 porocyte culture plates, every hole adds 2ml cell suspension (concentration is 1 * 10
7individual cell/ml), put cell culture incubator and cultivate 2h, after cell attachment, centrifugal, carefully remove supernatant.To every hole, add the serum-free medium that 2ml is fresh again.Add ginsenoside Rg1 to final concentration be 50 μ g/ml, put 37 ℃, cultivate 1h; Then add LPS to final concentration 1 μ g/ml, put 37 ℃, continue to cultivate after 20h, centrifugal rear collecting cell, extracts RNA, detects the mrna expression level of pro-inflammatory cytokine TNF-α, IL-1 β and IL-6 and inflammatory mediator iNOS and COX-2 by RT-PCR method.
The results are shown in Figure 14.Ginsenoside Rg1 can significantly reduce pro-inflammatory cytokine TNF-α, IL-1 β that LPS causes and the mrna expression level of IL-6 and inflammatory mediator iNOS and COX-2 as seen from Figure 14.
Embodiment 6: the interference effect of ginsenoside Rg1 to LPS and TLR-4 combination
Can in order to study Rg1, affect the combination of LPS and TLR4, we carry out immunofluorescence test with RAW264.7 cell.Figure 15 shows, when the LPS(HONGGUANG with Alexa fluor594 labelling) separately and during cell, be combined in TLR4(green glow) on LPS optical density higher (second row), and the TLR4 in after birth and kytoplasm all with LPS generation combination.When add Rg1 in RAW264.7 cell culture fluid, and while progressively improving Rg1 concentration, then adding the LPS with Alexa fluor594 labelling, the LPS HONGGUANG density being attached on TLR4 gradually reduces.This presentation of results adds Rg1 in RAW264.7 cell culture fluid, and Rg1 can be incorporated into the TLR4 receptor of RAW264.7 cell, hinders the combination of LPS and TLR4.More than experiment repeats three times, obtains identical result.
By this experiment, can obtain drawing a conclusion:
Cracking when gram negative bacteria is dead, discharge endotoxin LPS, and enter blood circulation.Lipopolysaccharide binding protein LBP in blood and LPS combination, pass to LPS the CD14 of Macrophage Surface, forms CD14-LPS.Myeloid differential protein-2(MD-2 in macrophage membrane) and Toll sample receptor 4(TLR4) in conjunction with forming MD2-TLR4, there is pattern recognition effect.After TLR4 identification LPS, form TLR4-MD2-LPS complex, the three-dimensional conformation of TLR4 changes, in its born of the same parents, the TIR domain of part is done to transduce with adaptin MyD88 effect enabling signal by homotype mutually, the adaptin TRAM that inclusive NAND MyD88 relies on and TRIF effect activate NF-к B, induction macrophage synthesizes and secretion IL-1, IL-6, the cytokines such as IFN-β and TNF-α, they enter after blood circulation arrives hypothalamus and act on thermotaxic centre, make to move on set point, cause organism fever.The inflammatory reactions such as these are discharged into extracellular cytokine and also cause granulocyte, macrophage Chemotaxis, and capillary permeability increases, lymphocytic infiltration.
After animal injection ginsenoside Rg1, Rg1 is attached to the TLR4 receptor of macrophage, the combination of LPS and TLR4 receptor while having blocked gram-negative bacterial infections, reduced the release of inflammatory cytokine and inflammatory mediator, make fervescence effect, and blood leucocyte rising effect reduces, reduced the toxic action of endotoxin LPS, thereby reduced any death that can cause endotoxin LPS to raise and cause such as gram-negative bacterial infections, produced therapeutical effect.
Finally, it is also to be noted that, what more than enumerate is only several specific embodiments of the present invention.Obviously, the invention is not restricted to above embodiment, can also have many distortion.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention, all should think protection scope of the present invention.
Claims (2)
1. ginsenoside Rg1 is being prepared the application of anti-endotoxin effect on Toll sample receptor 4 medicines.
2. ginsenoside Rg1 according to claim 1 is being prepared the application of anti-endotoxin effect on Toll sample receptor 4 medicines, it is characterized in that: described ginsenoside Rg1 can stop endotoxin to be attached to the Toll sample receptor 4 in mammalian body, thus the toxic action of blocking-up bacterial endotoxin.
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| CN102014941A (en) * | 2008-02-29 | 2011-04-13 | 阿费克萨生命科学公司 | Activation of innate and adaptive immune responses by a ginseng extract |
| CN101244280A (en) * | 2008-03-03 | 2008-08-20 | 复旦大学附属华山医院 | Interfere function of panaxoside Rg1 for self immunity myeloencephalitis mouse |
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